IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype
Takahiro Masuda1, Makoto Tsuda1, Ryohei Yoshinaga1
1Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
Abstract:
Microglia become activated by multiple types of damage in the nervous system and play essential roles in neuronal pathologies. However, how microglia transform into reactive phenotypes is poorly understood. Here, we identify the transcription factor interferon regulatory factor 8 (IRF8) as a critical regulator of reactive microglia. Within the spinal cord, IRF8 expression was normally low; however, the expression was markedly upregulated in microglia, but not in neurons or astrocytes, after peripheral nerve injury (PNI). IRF8 overexpression in cultured microglia promoted the transcription of genes associated with reactive states; conversely, IRF8 deficiency prevented these gene expressions in the spinal cord following PNI. Furthermore, IRF8-deficient mice were resistant to neuropathic pain, a common sequela of PNI, and transferring IRF8-overexpressing microglia spinally to normal mice produced pain. Therefore, IRF8 may activate a program of gene expression that transforms microglia into a reactive phenotype. Our findings provide a newly observed mechanism for microglial activation.
Insights
Interferon regulatory factor 8 (IRF8) drives microglial activation and neuropathic pain following nerve injury. IRF8 deficiency protects against pain, revealing a key mechanism in neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia, the immune cells of the central nervous system, become activated in response to neural damage and contribute to neuronal pathologies.
- The precise molecular mechanisms governing the transformation of microglia into reactive phenotypes remain incompletely understood.
Purpose of the Study:
- To identify key regulators involved in microglial activation and the development of neuropathic pain.
- To elucidate the role of transcription factors in mediating microglial responses to peripheral nerve injury (PNI).
Main Methods:
- Investigated the expression of transcription factor interferon regulatory factor 8 (IRF8) in microglia following PNI in a mouse model.
- Utilized in vitro cultured microglia to assess the functional impact of IRF8 overexpression on gene transcription.
- Assessed neuropathic pain behaviors in IRF8-deficient mice and evaluated the effects of microglia transplantation.
Main Results:
- IRF8 expression was significantly upregulated in spinal cord microglia after PNI, but not in neurons or astrocytes.
- IRF8 overexpression in microglia promoted the transcription of reactive genes, while IRF8 deficiency prevented these changes post-PNI.
- IRF8-deficient mice exhibited resistance to neuropathic pain, and transfer of IRF8-overexpressing microglia induced pain.
Conclusions:
- Interferon regulatory factor 8 (IRF8) acts as a critical regulator of microglial activation and the development of neuropathic pain.
- IRF8 appears to initiate a gene expression program that converts microglia into a reactive phenotype following nerve injury.
- These findings uncover a novel molecular mechanism underlying microglial activation in the context of neuronal damage and pain.
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